Differential Expression of Nitric Oxide Synthases in Bacterial Meningitis: Role of the Inducible Isoform for Blood-Brain Barrier Breakdown

• Published in: The Journal of infectious diseases Vol. 183; no. 12; pp. 1749 - 1759
• Main Authors: Winkler, Frank, Koedel, Uwe, Kastenbauer, Stefan, Pfister, H. Walter
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Chicago, IL The University of Chicago Press 15-06-2001; University of Chicago Press; Oxford University Press
• Subjects: Animals; Bacterial diseases; Bacterial meningitis; Bacteriology; Biological and medical sciences; Blood brain barrier; Blood-Brain Barrier - physiology; Blotting, Western; Chemokine CCL3; Chemokine CCL4; Chemokine CXCL2; Cytokines; Cytokines - metabolism; Experimental bacterial diseases and models; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Immunohistochemistry; Infections; Infectious diseases; interleukin 1^b; Leukocytes; macrophage inflammatory protein 1^a; Macrophage Inflammatory Proteins - metabolism; Major Articles; Male; Medical sciences; Meningitis, Pneumococcal - enzymology; Meningitis, Pneumococcal - genetics; Meningitis, Pneumococcal - metabolism; Messenger RNA; Mice; Mice, Inbred C57BL; Microbiology; Monokines - metabolism; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Oxides; Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains; Pneumococcal meningitis; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Streptococcus pneumoniae; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Up-Regulation; Immunohistochemistry; Molecular form; Transcription; Central nervous system; Synthase; Blood; Necrosis; Messenger RNA; Immunoblotting assay; Micrococcales; Bacteria; Meningitis; Nervous system diseases; Enzyme; Use; Rodentia; Nitric-oxide synthase; Streptococcus pneumoniae; Polymerase chain reaction; Streptococcaceae; Vertebrata; Mammalia; Mouse; Nitric oxide; Central nervous system disease; Oxidoreductases; Brain (vertebrata)
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/320730

The aim of the study was to determine the differential expression of nitric oxide (NO) synthase (NOS) isoforms and the pathophysiologic relevance of inducible NOS (iNOS) in experimental pneumococcal meningitis. By use of reverse transcription–polymerase chain reaction analysis, immunohistochemistry, and Western blotting, increased brain mRNA and increased protein levels of endothelial NOS (eNOS) and iNOS were detected 24 h after intracisternal pneumococcal inoculation. In iNOS-deficient mice, disruption of the blood-brain barrier (BBB) was significantly reduced, compared with that in wild-type mice. This beneficial effect of iNOS deficiency was associated with a lack of nitrotyrosine immunoreactivity. Furthermore, brain protein levels of interleukin (IL)–1β, IL-6, and tumor necrosis factor–α and brain mRNA levels of macrophage inflammatory protein (MIP)–1α and MIP-2 were significantly reduced in infected animals lacking iNOS. These findings suggest that (1) not only iNOS but also eNOS is up-regulated in the acute phase of experimental bacterial meningitis, and (2) iNOS-derived NO contributes to peroxynitrite formation and BBB breaching in this disease